Anoikis is a specific form of programmed cell death induced by the loss of cell contact with the extracellular matrix and other cells, and plays an important role in organism development, tissue homeostasis, disease development and tumor metastasis. We comprehensively investigated the expression patterns of anoikis-related genes (ARGs) in kidney renal clear cell carcinoma (KIRC) from public databases. Anoikis-related prognostic signatures were established based on four ARGs expression, in which KIRC patients were assigned different risk scores and divided into two different risk groups. In addition, four ARGs expression was validated by qRT-PCR. A better prognosis was observed in the low-risk group, but with lower immune activity (including immune cells and immune-related functions) in the tumor microenvironment. Combined with the relevant clinical characteristics, a nomogram for clinical application was established. Receiver operating characteristics (ROC) and calibration curves were constructed to demonstrate the predictive power of this risk signature. In addition, higher risk scores were significantly and positively correlated with higher gene expression of tumor mutation load (TMB), immune checkpoints (ICPs) and mismatch repair (MMR)-related proteins in general. The results also suggested that the high-risk group was more sensitive to immunotherapy and certain chemotherapeutic agents. Anoikis-related prognostic signatures may provide a better understanding of the roles of ARGs and offer new perspectives for clinical prognosis and individualized treatment.© 2023. Springer Nature Limited.